Weight management medications for chronic use in 37 veterans affairs medical centers—A medication use evaluation

Abstract Rationale Controlled trials have demonstrated successful weight loss associated with certain weight management medications (WMMs). However, there are limited real‐world data on prescribing patterns and efficacy and safety profiles of WMMs in Veterans Affairs (VA) patients. Objective To evaluate: utilization patterns of WMMs liraglutide, naltrexone/bupropion, orlistat, phentermine, phentermine/topiramate, and semaglutide; weight loss at three, six, twelve, and more than 12 months; safety; and treatment barriers. Methods A retrospective, cross‐sectional medication use evaluation (MUE) was conducted using electronic health records of outpatient Veterans newly initiated on WMMs at 37 VA Medical Centers between 1 March 2020 and 31 March 2022. Chart review was used to identify WMM utilization and capture rates of clinical response, defined as 5% and 10% or greater weight loss at the final weight, adverse drug events (ADEs), non‐adherence, and discontinuations. Site‐specific surveys evaluated local practices and barriers. Results Among 1959 eligible Veterans, semaglutide, phentermine/topiramate, and orlistat were most frequently prescribed. The clinical response was highest among phentermine/topiramate, liraglutide, and semaglutide. Naltrexone/bupropion and phentermine demonstrated the highest and lowest ADE rates, respectively. Potential barriers to WMM utilization and successful treatment by site reports were drug shortages, patient perceptions of therapeutic course, personal preferences, and VA WMM use criteria. Conclusions Smaller weight loss and higher discontinuation rates were observed relative to clinical trials. The MUE data allow for better assessment of benefits and risks for Veterans prescribed WMMs.


| INTRODUCTION
An estimated 78% of Veterans have a body mass index (BMI) in the overweight or obese categories, increasing their risk of diabetes, cardiovascular morbidity, certain cancer types, and lower quality of life. 1,2While physical activity, diet and behavior modifications are considered first-line treatments for obesity, patients may require Food and Drug Administration (FDA)-approved medications to achieve weight management goals.In patients with either BMI ≥30 kg/ m 2 or BMI≥27 kg/m 2 with obesity-related conditions, the Veterans Affairs (VA)/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity suggests offering weight management medications (WMMs) as adjunct therapy to comprehensive lifestyle interventions (CLI) (i.e., behavioral, dietary, and physical activity components). 1 Within the VA, CLI is formally delivered through the MOVE! weight management program as the primary mechanism for fulfilling CLI criteria.Patients may attend an approved non-VA CLI program, but this is not a typical occurrence.
WMMs available in the VA with Criteria for Use (CFU) at the time of the evaluation included phentermine/topiramate, orlistat, naltrexone/bupropion, liraglutide, and semaglutide.4][5] One retrospective analysis review of WMMs in the VA by Pendse et al. found efficacy results similar to other studies. 3Another VA database analysis by Grabarczyk (2018) assessed weight loss rates of orlistat, phentermine, and phentermine/topiramate when paired with the VA's MOVE! program compared with weight loss associated with the MOVE! program alone. 4The study showed that achievement of ≥5% weight loss after 20 or more weeks differed significantly among groups, ranging from 26.2% in the MOVE!-only group, to 40.3% in the phentermine-topiramate group.8][9][10][11] While there is evidence of successful weight loss with certain WMMs among Veterans, further real-world data are needed to assess the more recently approved semaglutide for chronic weight management.Marketed as WEGOVY® for weight loss, this drug was associated with significantly higher body weight change compared to placebo (−14.9% vs. −2.4%)[14][15][16][17] However, the mean age (46 years) and predominantly female population studied make these findings less applicable to the older and predominantly male VA population, hence, the need for investigation of WEGOVY®'s effects among Veterans.
Given the severity of certain adverse drug events (ADEs) associated with WMMs, there is a need to assess prescribing trends and observed patient experiences of WMMs in the VA.A medication use evaluation (MUE) is a systematic and interdisciplinary performance improvement tool that employs descriptive and exploratory analyses on medication utilization to identify operational needs in patient care with the goal of optimizing patient outcomes. 18The VA Center for Medication Safety (VAMedSAFE) conducts MUEs to assess safe and appropriate use of medications in Veterans through data abstraction of prescribing patterns and observed patient experiences.We conducted a multi-site MUE on prescribing patterns and reported outcomes of selected WMMs at 37 VA medical centers (VAMCs) to assess the safety and extent of weight loss achieved by each WMM to provide an informed risk-benefit assessment in a real-world setting.This MUE evaluated prescribing and utilization patterns of WMMs, weight loss at 3, 6, 12, and >12 months while on WMMs, and the safety of WMMs.Additionally, patient-and provider-specific barriers to achieving successful weight management were assessed.

| METHODS
A retrospective, cross-sectional evaluation of Veterans initiated on a WMM between 1 March 2020 and 31 March 2022 was conducted.
Initiation was defined as the absence of prescriptions for any of the six selected WMMs within 12 months prior to the index date, which was the earliest release date of the first WMM prescribed during the MUE timeframe.The release date indicates when the prescription was mailed or dispensed at the pharmacy.The MUE cohort was derived from a database extraction using outpatient prescription information from the VA Corporate Data Warehouse and applying specific criteria for weight loss indication (e.g., diagnosis of Type 2 diabetes mellitus, must have BMI ≥27 kg/m 2 , semaglutide (OZEM-PIC®) prescription label to include "for weight management"). 19luntary participation was solicited from all VAMCs.Sitespecific patient lists were provided to participating VAMCs (n = 37 sites).These lists contained incident users of the six WMMs (liraglutide, naltrexone/bupropion, orlistat, phentermine, phentermine/ topiramate, and semaglutide (WEGOVY® and OZEMPIC®).Pharmacists and postgraduate pharmacy residents at VAMCs manually reviewed patient charts to verify eligibility and collect information.
Participating sites were instructed to follow a standardized process for chart review and submission of de-identified data via a web-based Microsoft InfoPath® tool through a secure SharePoint portal.A chart review goal of 100 eligible Veterans was set per site.
This number was derived from a combination of feasibility and reasonably precise confidence intervals for the outcome "≥5% weight loss" based on literature estimates. 13,14,20,21For each eligible case, all subsequent WMMs prescribed during the MUE timeframe were assessed to capture potential switches.
To be eligible, the Veteran must have received at least one WMM during the MUE timeframe and had a recorded baseline weight and BMI of ≥27 kg/m 2 within 120 days prior to the index date.Review of past medical history spanned 24 months prior to the index date.Specific ADEs, medication discontinuation, and weight program, reviewers could include other approved non-VA CLI programs.Suicidal history was collected from provider notes in the 24 months prior to the index date, although the event described may have taken place before this timeframe.Information on dosing, place in therapy, and therapeutic transitions between any of the six WMMs during the MUE timeframe were collected.Proportion of Veterans remaining on each WMM was calculated for <3 months, 3 to <6 months, 6 to <12 months, or ≥12 months, along with documented adherence.Recorded weights at baseline, 3, 6, and 12 months were collected for each WMM, as applicable, including an overall final weight.Due to the SARS-CoV-2 pandemic necessitating virtual patient visits, we accepted self-reported and clinic-measured weights.
Safety measures included the ADE rate for each WMM as well as discontinuation rates, inclusive of reasons.To reflect actual patient usage, medication adherence was first based on provider notation.If provider notation was missing, the reviewer calculated the Medication Possession Ratio (MPR); an MPR is calculated as the sum of days' supply dispensed in a time period divided by the days in that period and reported as a percentage.An MPR≥80% was considered adherent.
Following chart review, participant facilities completed a survey evaluating local practices and policies on WMM prescribing and drug shortage management strategies as well as patient-and providerspecific barriers to the optimal use of WMMs.
VAMedSAFE conducted aggregate analysis of abstracted data.
Site data were combined to produce national totals and median values, with percentages and 95% confidence intervals as appropriate.Descriptive statistics were used to report on the main variables of interest.To control for potential variation in weight measurement methods, weight differences were calculated only for matched weight documentation methods (clinic or self-report).
Across a broad range of variables, we saw no consistent trends between the groups with clinic-measured or self-reported weight differences, so the groups were not separated in the results.Weeks of therapy, when missing, were estimated using available dates.Due to the descriptive nature of an MUE, potential confounding effects were not addressed.
All protected health information (PHI) was maintained behind the VA firewall.The patient lists contained a crosswalk to assigned non-identifiable IDs used for all data submission.This MUE was deemed a quality improvement project by the Edward Hines, Jr., VA Institutional Review Board and met exemption criteria based on VA Program Guide 1200.21. 22All participant sites signed data use agreements.

| RESULTS
Thirty-seven VAMCs participated in the MUE.Of 3629 Veterans initiated on a WMM during the MUE timeframe and assigned for review, 1670 patients (46%) were excluded, mainly due to not having chronic weight management as the primary indication for the WMM.
Half of the excluded patients did not have a baseline weight recorded in the chart, and about one-third did not have a baseline BMI ≥27 kg/ m 2 .The final MUE cohort consisted of 1959 Veterans meeting eligibility criteria (Figure 1).
The eligible cohort was mostly male and Caucasian with a median age of 51 years at index date (Table 1).The most common comorbidities identified were psychiatric diagnosis (61%), hypertension (54%), obstructive sleep apnea (47%), and dyslipidemia (43%).Most patients were categorized as Class III obesity (48%), followed by 31% and 21% for Class II and Class I, respectively.The median baseline weight and BMI were 118 and 39 kg/m 2 , respectively (Table 2).Most Veterans participated in at least one visit to the MOVE! or other approved CLI program.
Patients who received semaglutide, liraglutide, and phentermine/ topiramate had the highest proportion achieving ≥5% or ≥10% weight loss at the final weight recorded (Table 4).While there was variation in the extent of reported weight loss for each WMM, the rate of weight loss per week appeared similar across WMMs (Table 4).Gastrointestinal ADEs were the most frequently reported among all medications except phentermine (Table 5).Other ADEs differed in frequency across the different WMMs.Discontinuation secondary to ADE ranged from 12% to 29%.Discontinuation for any reason, including ADEs, was most frequently documented for orlistat (80%) and naltrexone/bupropion (75%).
Considering the high proportion of patients with psychiatric comorbidities in the MUE cohort, subgroup analyses were conducted to evaluate the occurrence of certain mental health ADEs in patients with and without predisposing past medical histories.Specifically, we attempted to evaluate psychotic symptoms ADE in patients with and without a past medical history of schizophrenia spectrum and other unspecified psychotic disorders, as well as suicidal ideation/suicide attempt (SI/SA) while receiving WMM in patients with and without a history of SI/SA.However, due to the low number of events recorded, we were unable to derive meaningful findings.

| DISCUSSION
4][5] Our evaluation of the six WMMs provides additional information on treatment selection, patient response, adherence and ADEs in a representative population of Veterans receiving care across 37 VA medical centers.
Weight reduction consistent with the hierarchy of benefit based on published literature was observed with each of the evaluated WMMs.However, the extent of weight reduction, or percent of the population with clinically meaningful weight reduction of at least 5%, did not reflect those reported in clinical trials, whereas the discontinuation rate due to an ADE was higher in this MUE cohort (Table 7). 13,20 general, reported ADEs were similar to those in published information.Limited data exists with the use of WMMs in patients with a history of mental illness including major depressive disorder, The most common psychiatric diagnoses found included anxiety, bipolar disorder, depression, psychosis, and schizophrenia.WMM use in patients with psychiatric diagnosis was of interest as there is limited data available in the literature.In light of the WMM clinical trial exclusion criteria, bipolar and psychosis disorders were evaluated as a separate subset of psychiatric diagnoses to inform on potential modifications to national criteria for use.Within VA, participation in CLI is a criterion for the use of the WMMs and is primarily achieved through the MOVE! program.According to the MUE results, 88% of patients were documented as having attended MOVE! or another approved CLI.These patients had a greater proportion who achieved a ≥5% weight reduction when compared to those who did not (49% vs. 37%).
In this MUE, 79% of patients treated with WMMs were within Class II (severe) or III (more severe) obesity at baseline.This may reflect providers prioritizing medication management in these higher classes of obesity.Additionally, patients with elevated BMIs were more likely candidates for first-line therapy with the in-demand GLP-1 agonist medication.
We observed a large proportion of patients who discontinued therapy prior to 3 months.A plausible explanation may be attributed to the Veteran's weakened adherence from a perceived lack of efficacy during the early months.This was observed in a 2024 cohort study, which found a 6% increase in odds of remaining adherent if there was a 1% weight loss improvement at 6 months. 23e post-MUE site survey provided insight for guiding future VA academic detailing efforts.VA Academic Detailing is an internal program that supports VA health care professionals through education on current, evidence-based treatments and resources to ensure consistent, high-quality care across all sites. 24The survey under-  3 (0-7)  4 (0-11)  1 (−1 to 3)  3 (0-7)  5 (0-10)  8 (2-5 The final weight was defined as the most recent weight while the Veteran was receiving the WMM.The final weight may have occurred after the MUE timeframe.
Caution should be exercised in making comparisons between WMMs as the findings reflect how these WMMs performed as used within the VA system.Existing biases as well as lack of randomization and controls prevent a direct comparison of effectiveness and safety outcomes between WMMs.The prescribing patterns and observed trends in safety and effectiveness, however, can be used as data to support planning for future use of each WMM.

| CONCLUSION
This MUE presents practical insight regarding the safety and weight loss potential of WMMs among the older and predominantly male Veteran population.We found a lower percentage of weight loss and assessed from the index date through WMM discontinuation or the end of the evaluation period, as applicable.Discontinuation was determined by provider documentation, any self-reported discontinuation, or absence of subsequent prescription release dates.Temporal association of an event with no clear alternative etiology satisfied the condition for ADE attribution to the WMM as determined by the reviewer.To standardize reporting of increased heart rate (HR) and elevated blood pressure (BP) as ADEs, we pre-defined this as HR > 100 bpm, and either systolic BP > 160 mmHg or diastolic BP > 100 mmHg without prior occurrence during the 30 days before WMM initiation.Aggregated chart review data were used to describe prescribing and utilization patterns.The following measures were collected: baseline recorded weight and BMI prior to index date, documented participation in VA MOVE! or other approved non-VA CLI, obesityrelated comorbidities, and use of concomitant medications associated with weight gain.While CLI primarily consists of the VA MOVE!
Thirty-six VAMCs participating in the MUE responded to the post-MUE survey on local practices (Table 6).A common obstacle encountered was the semaglutide shortage during the MUE timeframe.The most common shortage management strategy was not permitting new-starts (n = 20 sites) as per national VHA guidance.Fifty-three percent of sites reported using off-label semaglutide (OZEMPIC®) for weight loss alone.Sites responded that noticeable patient barriers to successful weight management included misunderstanding of the importance of continued lifestyle intervention (n = 15 sites), expectation of medication efficacy exceeding actual weight loss attained (n = 15 sites), and weight loss plateau (n = 13 sites).Among prescribing barriers, drug shortages (n = 20 sites), inadequate participation (n = 18 sites) or documentation (n = 11 sites) of CLI as required by CFU, patient preference (n = 11 sites), provider preference (n = 10 sites), and denied prior authorization (n = 8 sites) were identified.

F
WALCZUKET AL.  other serious psychiatric disorders, or history of suicidal attempt or recent suicidal behavior or ideation, as these conditions were excluded in clinical trials.It is therefore important to note the high percentage of patients in the MUE cohort with psychiatric comorbidity at baseline (61%), indicative of the high prevalence of mental illness among Veterans.The MUE specifically evaluated ADEs of psychotic symptoms reported during use of the WMM in a cohort of patients with and without a past medical history of schizophrenia spectrum and other unspecified psychotic disorders, as well as reports of suicidal attempts or ideation while receiving the WMM in a cohort of patients with or without a history of suicidal attempt or ideation.No safety signals surfaced from this evaluation.This may be due to the small number in each subgroup as well as prescriber avoidance of higher-risk medications in patients with psychiatric conditions.At the time of the MUE, naltrexone/bupropion, orlistat, and phentermine/topiramate were on the VA National Formulary (VANF) with prior authorization based on national CFU.VANF is a dynamic

c
The percentage describes the proportion of Veterans who received the WMM as a first line agent among all Veterans who received the specific WMM during the MUE timeframe.list of all medications available throughout the entire VA system.While items listed on the VANF are covered by VA pharmacy benefits, products with a prior authorization require additional review by an adjudication body.The national CFU guidance assists practitioners in clinical decision-making to standardize and improve the quality of patient care.Liraglutide (SAXENDA®) and semaglutide (WEGOVY®) were available on a non-formulary basis in accordance with the national CFU.Phentermine was available as a non-formulary agent without national CFU.In general, the VANF medications are to be considered prior to non-formulary agents.This was reflected in the high percentage of first line use of naltrexone/bupropion (86%), orlistat (88%), and phentermine/topiramate (90%).The relatively high use of first-line therapy with the non-formulary agents liraglutide (SAXENDA®) (74%) and semaglutide (WEGOVY®; and off-label use of VANF Ozempic®) (70%) is likely due to satisfying criteria for first-line therapy based on BMI or other comorbidities.These prescribing patterns were used to inform the discussion of the VA National Formulary Committee on projected utilization and formulary management.
scored the importance of patient communication regarding realistic expectations for weight loss and necessary long-term therapy commitments as well as the importance of CLI.The prescribing barriers were shared with the VA National Formulary Committee, MOVE!, and VA Academic Detailing leadership.This resulted in several of these barriers being addressed in the Weight Management Academic Detailing materials.Moreover, a frequently asked questions (FAQ) document was developed in collaboration with MOVE! to address −/þ kg, median (IQR)

a
higher discontinuation rate due to ADEs compared with those reported in clinical trials.However, Veterans experienced beneficial weight loss, particularly with semaglutide, phentermine/topiramate, and liraglutide.Therefore, the MUE data allow for better assessment of benefits and risks for Veterans prescribed WMMs and underscore the need for improved patient and provider education regarding therapy expectations and the importance of CLI.Further plans will include safety monitoring with a focus on psychiatric and other ADEs, improvements in processes such as appropriate and equitable prescribing of first line GLP-1 agonists, and evaluation of new WMMs.AUTHOR CONTRIBUTIONSSamanthaWalczuk -Conducted the project, educated chart reviewers, interpreted data, drafted manuscript.Muriel Burk -Managed the project, developed protocol, designed data abstraction tool, coordinated efforts with participant sites, interpreted data, and drafted manuscript.Elaine Furmaga -Served as a clinical consultant and subject matter expert, developed the MUE protocol, interpreted data, and contributed to manuscript write-up.Samaneh Ghassemi -T A B L E 7 Comparison of observed results and published literature.
2271 the unit of analysis for this table represents medication exposures since patients may have received one or more WMM during the MUE timeframe.Adherence was determined through documented provider assessment in progress notes.If no comments were found, the reviewers calculated a Medication Possession Ratio (MPR).An MPR of 80% or greater was determined to be adherent, while an MPR below 80% would indicate non-adherence.
a Multiple reasons may have been selected for WMM discontinuation.bOnly evaluated for semaglutide.ca Sites may select multiple responses for each question.ications in patients with mental health history or prior social habits.This could result in fewer events of interest with the higher-risk medications.Another source of potential bias is the VA GLP-1 agonist CFU requiring intolerance or inadequate response to two prior formulary agents.Providers may have a lower threshold for attributing adverse events to formulary agents to qualify a patient